Effect of Zuoxingdan Injection on Patients with Heart Failure After Myocar- Dial Infarction and Its Effects on Nt-Pro Bnp, Lvedd, and Lvef

Acta Medica Mediterranea, 2019, 35: 2167

EFFECT OF ZUOXINGDAN INJECTION ON PATIENTS WITH HEART FAILURE AFTER MYOCAR- DIAL INFARCTION AND ITS EFFECTS ON NT-PRO BNP, LVEDD, AND LVEF

Shu-guang Zhang1, #, Jiu Jiang2, #, Xu Han3, * 1Huai’an Hospital Affiliated to Nanjing University of Chinese Medicine, No.3, Heping Rd, Huai’an, Jiangsu Province, China, 223001 - 2Cardiology Department, Lianshui County People’s Hospital, No. 6, Hongri Avenue, Lianshui County, Jiangsu Province, China 223400 - 3Affiliated Hospital of Nanjing University of Chinese Medicine, No.155, Hanzhong Rd, Qinhuai District, Nanjing, Jiangsu Province, China, 210001 #These authors contributed equally to this work ABSTRACT

Objective: To investigate the efficacy of Levosimendan on the treatment of heart failure after myocardial infarction and the serum N-terminal pro-brain natriuretic peptide (NT-pro BNP), left ventricular end-diastolic diameter (LVEDD), and the impact of the left ventricle ejection fraction (LVEF). Methods: Eighty-six patients with heart failure after myocardial infarction in our hospital from December 2014 to December 2016 were randomly divided into treatment group and control group with 43 cases in each group. On the basis of conventional treatment, the control group was given milrinone injection, and the treatment group was treated with levosimendan injection for one week. The clinical effects of the two groups after treatment, the changes in the serum NT-pro BNP, LVEDD, LVEF levels, and the occurrence of adverse reactions were compared. Results: The total effective rate of the treatment group after treatment was higher than that of the control group (90.70% vs. 67.44%) and the difference between the two groups was statistically significant (P<0.05). After treatment, serum NT-pro BNP, LVEDD, and LVEF were improved compared with those before treatment, but the treatment group was more obvious (P<0.05). The levels of serum IL-6, Hs-CRP, and TNF-α in the two groups were significantly lower than those before treatment (P<0.05). The levels of serum IL-6, Hs-CRP, and TNF-α in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P<0.05). The incidence of adverse reactions in the treatment group was lower than that in the control group, but the difference was not statistically significant (P>0.05). Conclusion: Levosimendan injection has obvious curative effects on heart failure after myocardial infarction, and effectively regulates the changes in the serum NT-pro BNP, LVEDD, and LVEF levels, enhancing myocardial contractility and reducing the incidence of adverse reactions, which is safe and reliable.

Keywords: Levosimendan, heart failure after myocardial infarction, NT-pro BNP, LVEDD, LVEF.

DOI: 10.19193/0393-6384_2019_4_339

Received December 30, 2018; Accepted March 20, 2019

Introduction inotropic drug that does not increase myocardial oxygen consumption while relieving symptoms. It Heart failure (HF) is a common and frequent- can improve blood pumping function, increase my- ly-occurring disease in the Cardiology Department, ocardial contractility, and also dilate blood vessels, where the heart function is too weak to meet the thereby improving clinical symptoms(2-3). To further needs of various organs in the body, resulting in analyse the clinical significance of levosimendan difficulty to exhale and fatigue. Generally, the injection in the treatment of heart failure, this study treatments of cardiac functions, diuretic, and vas- used milrinone and levosimendan injection to treat odilating agents often fail to improve or worsen heart failure patients on the basis of conventional the symptoms, which is a major problem in clinical drug use and to explore the serum NT-pro effects practice(1).Levosimendan is a new type of positive on the changes in BNP, LVEDD, and LVEF levels. 2168 Shu-guang Zhang, Jiu Jiang et Al

Materials and methods for one week. The blood pressure, heart rate, and electrocardiogram were monitored regularly, and General Information symptomatic treatment was performed if abnormal. A total of 86 patients with heart failure in our department of cardiology from December 2014 to Observation indicators December 2016 were selected. Inclusion criteria • According to the New York Heart Associa- included Diagnosis of heart failure, conditions that tion (NYHA) heart failure grading standard were difficult to control with the use of regular an- Markedly effective: patients are identified with ti-heart failure drugs; a heart failure grading stand- shortness of breath, cyanosis, fatigue, cold limbs ard according to the New York Heart Association and the resolution of other symptoms, normal ECG, (NYHA)(4), cardiac function in grade III–IV. Exclu - heart function classification is improved by level 2 sion criteria included severe hepatic and renal dys- or higher; effective: patients have some symptoms function (blood test transaminase increased; serum resolved, the electrocardiogram is improved, and creatinine clearance rate≤30 ml/min); severe water the cardiac function is improved to grade 1; inva- and electrolyte disorders (potassium>5.5 mmol/L or lid: the cardiac function grade is not improved but potassium < 3.5 mmol/L; sodium<135 mmol/L or aggravated. Total efficiency = significant efficiency sodium>145 mmol/L); low blood pressure (systolic + efficiency. blood pressure <90mmHg); severe cardiopulmonary • N-terminal B-type brain natriuretic peptide dysfunction, (such as heart valve disease, implant - (NT-proBNP) was monitored by electrochemilumi- ed cardiac pacemaker, pulmonary heart disease and nescence, left ventricular end-diastolic diameter pericardial disease). There were 50 males and 36 fe- (LVEDD) level by cardiac colour Doppler ultrasound, males, aged 58–76 (68.5±7.2) years old. According left ventricular ejection fractions (LVEF) cardiac in- to the NYHA classification: 47 cases were of grade dex (CI), and left ventricular diastolic E peak/A peak III, and 39 cases were of grade IV. 86 patients were (E/A) ratio by echocardiography detection. randomly divided into two groups, the control group, • Serum inflammatory cytokines interleukin-6 and the treatment group. There were no significant (IL-6) and tumour necrosis factor-α (Tumour Ne- differences in age, gender, and cardiac function stag- crosis Factor, TNF-α) levels were detected by en- ing between the two groups (P>0.05). zyme-linked immunosorbent assay, and C-reactive protein was determined by immunoturbidimetric Cardiac function Group Sex n Age (year) stage assay (C-reactive protein, CRP). • Adverse reactions Male 25 Ⅲ 21 The level of blood pressure during the treat- The control group 68.51±7.35 ment, the speed of the heart rate, whether there are Female 18 Ⅳ 22 palpitations, the detection of liver and kidney function, and urine output. Male 27 Ⅲ 26 Therapy group 69.36±6.91 Statistical methods Female 16 Ⅳ 17 The data were analysed by SPSS 19.0 statisti - Table. 1: Comparison of age, gender, and cardiac function cal software. The measurement data were expressed staging between the two groups of patients (example). by (x̅±s), t-test was applied, and the Chi-square test (χ²) was applied to the count data. P<0.05 was con- Method sidered statistically significant. On the basis of conventional treatment, the control group used milrinone injection, and the first Results intravenous injection was 25-75 μg/kg for 10min, and then pumped continuously for 0.3 h with an Comparison of the clinical efficacy intravenous pump at 0.375 μg/kg per minute; the After one week of drug treatment, the total effec- treatment group was injected with an intravenous tive rate of patients treated with levosimendan injec- bolus injection of levosimendan injection, with the tion was as high as 90.71%, while the total effective first dose being injected at a loading dose of 12 μg/ rate of the control group treated with milrinone injec- kg for >10 min, then maintained at 0.1 μg/kg per tion was only 67.44%, the difference in treatment was minute. The two groups were treated continuously statistically significant (P < 0.05) (Table 2). Effect of zuoxingdan injection on patients with heart failure after myocardial infarction and its effects... 2169

Markedly Total Group n Time Hs-CRP TNF-α IL-6 Group n effective Effective Invalid efficiency (µmol/L) (pg/mL) (ng/L)

Before 28.73±9.25 208.63±68.18 41.18±8.26 The control 43 19 10 14 29 (67.44) treatment group Treatment 43 After  90.45±23.73* 19.45±5.24* treatment 10.42±4.25* Therapy group 43 26 13 4 39 (90.71) * Before treatment 29.16±8.84 214.44±72.22 42.13±8.44 Table. 2: Comparison of the clinical efficacy between the Control 43 After two groups of patients (%). treatment 17.62±5.73* 144.27±48.76* 27.47±5.63* *Indicates P<0.05 compared with the control group. Table. 4: Comparison of serum IL-6, Hs-CRP and TNF-α Comparison of serum NT-pro BNP, LVEDD, levels in the two groups. * and LVEF levels before and after treatment and Note: P<0.05 compared with the same group before treatment; P<0.05 compared with the control group after treatment. the ratio of LVEF and related indicators to the heart index (CI) and (E/A) Comparison of the adverse reactions Before treatment, there was no significant During the treatment period, there were symp- difference in serum NT-pro BNP, LVEDD, LVEF, toms such as blood pressure drop, headache, dizzi - and CI between the two groups (P >0.05). After ness, and palpitations in both groups, no death oc- treatment, the changes of serum NT-pro BNP and curred. The treatment of the symptoms did not affect LVEDD in the two groups were lower than those be- the treatment. The adverse reactions in the treatment fore treatment, and the treatment group was signifi- group were lower than those in the control group, cantly lower than that of the control group (P<0.05). but the difference was not statistically significant After treatment, the changes of LVEF and CI lev- (P>0.05) (Table 5). els in the two groups were significantly higher than Total those in the control group (P<0.05), but there was no Group H h P A F p Hy S G incidence significant change in the E/A values between the two Control 1 2 2 2 1 1 1 1 1 27.9% groups (P >0.05) (Table 3).

Treatment 1 2 0 1 1 0 1 1 0 16.2% NT-proBNP Group n Time (pg/ml) LVEDD LVEF CI E/A Table. 5: Comparison of the adverse reactions during treatment in the two groups of patients (example). 4 Before treatment 6548±450 78.70±7025 0.27±0.31 2.11±0.51 0.61±0.28 Notes: H, Hypotension; h, headache; P, Paroxysmal atrial fi- brillation; A, Arrhythmia; F, Frequent ventricular contraction; Control p, palpitation; Hy, Hypokalaemia; S, Sinus tachycardia; G, Ga- 3 After * 62.47±6.26* 0.38±0.22* 2.77±0.32* 0.62±0.26 treatment 1022±257 strointestinal reaction. Discussion Before 4 treatment 6542±447 79.09±7.33 0.25±0.32 2.07±0.50 0.57±0.25

Therapy Heart failure is caused by various reasons such

After * * * * 3 522±125 57.30±6.25 0.47±0.36 2.97±0.36 0.63±0.26 as myocardial contractility or diastolic dysfunction treatment where cardiac output is reduced and cannot meet the Table. 3: Comparison of NT-pro BNP, LVEDD, and needs of the body's metabolism, leading to breathing LVEF levels before and after treatment (x̅±s). difficulties, fatigue, oedema, palpitation, and other Note: *P<0.05 compared with before treatment; P<0.05 com- symptoms. The inflammatory response is one of the pared with the control group. important pathogenesis of the cardiovascular disease, and the occurrence of heart failure is also related to Comparison of serum IL-6, Hs-CRP and the activation of inflammatory cytokines. The contin- TNF-α levels in the two groups uous development of society, changes in environmen- The levels of serum IL-6, Hs-CRP and TNF-α tal climate, and some biochemical factors have led to in the two groups were significantly lower than an increase in the incidence of various cardiovascular those before treatment (P<0.05), and the levels of diseases. Although the medical level has improved to serum IL-6, Hs-CRP and TNF-α in the treatment some extent, heart failure, as the final stage of cardi- group were lower than those in the control group. ovascular disease, has a rising incidence and has be- Obviously, the difference was statistically signifi- come one of the major diseases that endanger human cant (P<0.05) (Table 4). health(5). Studies have shown that the current clini- 2170 Shu-guang Zhang, Jiu Jiang et Al cal treatment of heart failure is mainly based on the the continuous action of levosimendan, BNP, serum routine use of cardiac diuretic vasodilator drugs plus IL-6, Hs-CRP, and TNF-α can be reduced and the milrinone injection, but the total clinical effective rate inflammatory factors inhibited, thereby inhibiting of treatment is only 67%, and there is some damage myocardial remodelling, reducing serum NT-pro to hepatic and renal function (6-7). Therefore, there is BNP levels, and slowing the progression of heart an urgent need for further analysis to study the com- failure. Clinically, in the diagnosis of acute myo- bined use of anti-heart failure drugs and the selection cardial infarction, LVEF and LVEDD are calculated of drugs to improve efficiency. by cardiac colour Doppler ultrasound, which is used Levosimendan is a new generation of calcium to judge the abnormal changes of systolic function, sensitisers, which directly binds to the terminal re- cardiac ischaemia, resulting in decreased cardiac gion of cardiac troponin C (TnC), and can stabilise contractility and effective contraction, where the TnC in the presence of Ca2 + to promote the confor - size of cardiac contractility is closely related to the mation of myocardial contraction, thereby enhancing area of myocardial ischaemia; IL-6 is an auxiliary myocardial contractility and increasing cardiac out- indicator for the diagnosis of heart failure and has put to improve the haemodynamics and heart failure negative use in the detection of muscle strength and symptoms(8). In recent years, many clinical studies cytotoxicity; Hs-CRP is a sensitive biochemical in- have shown that levosimendan is effective in treating dicator of body inflammation; TNF-α helps regulate heart failure after myocardial infarction, can reduce the immune function and metabolic processes of cy- blood pressure in patients with heart failure, control tokines in the body, and its elevated levels in serum the spread of inflammation, and the incidence of ad- can aggravate the occurrence of heart failure; The verse reactions is extremely low (9-10). Studies have results of this study showed that there is a close rela- also shown that levosimendan can dilate the periph- tionship between serum NT-pro BNP, LVEDD, and eral blood vessels of the human body, thereby dilating LVEF. The changes of serum NT-pro BNP, LVEDD, the blood vessels around the kidneys, increasing renal and LVEF and serum IL-6 (12), Hs-CRP, and TNF-α blood flow, and possibly achieving protection against levels can accurately reflect cardiac function after kidney failure (11). The results of this study showed acute myocardial infarction, aid in the early evalu - that the total effective rate was 90.71% in the treat- ation of prognosis, and have high clinical value (13). ment group and 67.44% in the control group and the After treatment, serum NT-pro BNP, LVEDD, and treatment group was significantly better than the con- LVEF were significantly improved compared to be- trol group with improved serum NT-pro BNP levels, fore treatment. The levels of serum IL-6, Hs-CRP, LVEDD, LVEF, and CI. The reaction rate was also and TNF-α were significantly lower than those be- significantly lower in the treatment group compared fore treatment, but the serum levels of NT-pro BNP, to the control group. The damage to hepatic and renal LVEDD, and LVEF and serum IL-6, Hs-CRP, and function was minimal, and the symptoms of dyspnoea TNF-α were significantly improved in the treat - in patients were quickly relieved, and the safety and ment group (P<0.05). It would be more beneficial tolerability were good. During the treatment of levo- to show that levosimendan injection can help reg- simendan, the main adverse reactions are dizziness, ulate the changes of serum NT-pro BNP, LVEDD, decreased blood pressure, and palpitations, which and LVEF levels, enhance myocardial contractility, are mainly caused when the infusion is too fast or the improve dyspnoea, and other symptoms. This also dosage is too much. However, after adjustment, the shows that the changes in serum levels of NT-pro symptoms can be controlled. BNP, LVEDD, and LVEF have important clinical As a new generation of anti-heart failure drugs, value for early detection of heart failure(14-15). Levosimendan has been discussed by many aca - In conclusion, Zuoxingdan injection has a sig- demics, but there are few studies of its effects of the nificant effect on the treatment of heart failure after serum levels of NT-pro BNP, LVEDD, and LVEF. myocardial infarction, rapidly relieves symptoms, Serum NT-pro BNP is currently the best biochemical does not increase myocardial oxygen consumption, indicator for the management of heart failure, espe- and has good safety and tolerance. However, it is cially in the differential diagnosis of heart failure, still necessary to observe the prognosis of patients risk rating, prognosis, and treatment monitoring. In for a long time. The difference in the effect of lev- addition, levosimendan also has an anti-inflamma - osimendan on different degrees of heart failure still tory function, lowering serum cytokine function, re- requires further clinical trials in order to make Lev- ducing cardiac load, and protecting the heart. Under osimendan more widely used in clinical treatment. Effect of zuoxingdan injection on patients with heart failure after myocardial infarction and its effects... 2171

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